Herpes simplex virus (HSV), types 1 and 2, causes recurrent infections that range in severity from benign to serious. HSV emerges from latency in neurons to infect the skin and other tissues in the presence of a competent cellular immune system. The D glycoprotein (gD) of HSV, a transmembrane protein located in the virion envelope, initiates infection by binding to cellular receptors (Spear et al. (1993) Viral Fusion Mechanisms. Ed. Bentz. CRC press, Boca Raton). Recently, a cellular protein used by HSV for infection was identified and given the term HSV entry mediator (HVEM) (Montgomery (1996) Cell 87:427). HVEM is a transmembrane type 1 protein with a cysteine-rich extracellular domain that exhibits significant homology with receptors for tumor necrosis factor (TNF;)-related cytokines (Smith et al. (1994) Cell 76:959; Ware et al. (1995) in, Pathways of Cytolysis. Eds. Griffiths and Tschopp. Springer-Verlag, Basel). Many of the TNF superfamily members initiate a variety of cellular responses necessary to mount effective inflammatory and immune responses.
TNF is a type 2 transmembrane protein (Pennica (1984) Nature 312:724) that is proteolyzed to form the secreted protein (Black (1997) Nature 385:729), whereas LTα lacks a transmembrane domain (Gray (1984) Nature 312:721) and is exclusively secreted as a homotrimer (in this form it was also known as TNFβ). When expressed as a surface protein, LTα is associated with a 33 kDa protein (Androlewicz (1992) J. Biol. Chem. 267:2542), termed LTβ (Browning (1993) Cell 72:847), also a type 2 transmembrane glycoprotein, in heterotrimers of α1β2 and α2β1 subunit ratios (Androlewicz (1992) supra; Browning (1996) J. Biol. Chem. 271:8618). LTα and TNF both bind and signal through two receptors, the 55-60 kDa TNF receptor (TNFR60; CD120a or type 1) (Schall (1990) Cell 61:361; Loetscher (1990) Cell 61:351) and the 75-80 kDa TNFR (TNFR80; type 2 or CD120b) (Smith (1990) Science 248:1019). By contrast, the surface LTα1β2 complex is recognized specifically by the LTβ receptor (LTβR) (Crowe (1994) Science 264:707), which does not bind either LTα or TNF (Crowe (1994) supra) whereas both TNFRs bind the LTα2β1 heterotrimer (Crowe (1994) supra; Browning (1995) J. Immunol. 154:33).
Genetic deletions of LTα and LTβ genes in mice have revealed roles for these two genes in the development of lymph nodes and Peyer's patches (De Togni (1994) Science 264:703; Banks (1995) J. Immunol. 155:1685), and along with TNF and TNFR60, are also critical cytokines controlling the formation of germinal centers and immunoglobulin isotype switching (e.g., IgA production) during immune responses in adults (Matsumoto (1996) Science 271:1289; Mariathasan (1995) J. Inflammation 45:72). Most studies have pointed towards the LTα1β2/LTβR as the critical cytokine-receptor system controlling these functions (Crowe (1994) Science 264:707; Koni (1997) Immunity 5:491; Ettinger (1996) Proc. Natl. Acad. Sci. USA 93:13102; Rennert (1996) J. Exp. Med. 184:1999).